US5336771A - Certain 3,4-dihydro-2H-pyrano[2,3-b]pyridines - Google Patents

Certain 3,4-dihydro-2H-pyrano[2,3-b]pyridines Download PDF

Info

Publication number
US5336771A
US5336771A US07/961,049 US96104992A US5336771A US 5336771 A US5336771 A US 5336771A US 96104992 A US96104992 A US 96104992A US 5336771 A US5336771 A US 5336771A
Authority
US
United States
Prior art keywords
formula
compound
reaction
alkyl
pyrano
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US07/961,049
Inventor
Charles W. Murtiashaw
George J. Quallich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Inc
Original Assignee
Pfizer Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc filed Critical Pfizer Inc
Priority to US07/961,049 priority Critical patent/US5336771A/en
Assigned to PFIZER INC. reassignment PFIZER INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MURTIASHAW, CHARLES W., QUALLICH, GEORGE J.
Application granted granted Critical
Publication of US5336771A publication Critical patent/US5336771A/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to processes and intermediates for the preparation of spiro-heteroazolones.
  • the latter compounds are useful as aldose reductase inhibitors.
  • the present invention relates to a compound of the formula ##STR1## wherein B is hydroxide, chloro or bromo.
  • the present invention also relates to a compound of the formula ##STR2## wherein R 3 is hydrogen or (C 1 -C 4 )alkyl
  • the present invention also relates to a compound of the formula ##STR3## wherein R 3 is (C 1 -C 4 ) alkyl; Q is chlorine, bromine, or fluorine or OX, wherein X is SO 2 R 4 and R 4 is (C 1 -C 4 )alkyl, trifluoromethyl or phenyl optionally substituted with 1 to 3 substituents independently selected from (C 1 -C 4 )alkyl, chloro and nitro; and Z is a negative charge, hydrogen, or an oxygen protecting group (e.g., a silyl-containing group such as t-butyldimethylsilyl).
  • R 3 is (C 1 -C 4 ) alkyl
  • Q is chlorine, bromine, or fluorine or OX, wherein X is SO 2 R 4 and R 4 is (C 1 -C 4 )alkyl, trifluoromethyl or phenyl optionally substituted with 1 to 3 substituents independently selected from (C 1 -C
  • the present invention also relates to a pure enantiomer of a compound of the formula ##STR4## wherein R 3 is (C 1 -C 4 ) alkyl.
  • the present invention also relates to a compound of the formula: ##STR5## wherein R 3 is methyl and wherein the stereochemistry of the carbon at position 3 is pure in an absolute sense and may be of either the R or S configuration.
  • the present invention also relates to a process for preparing a compound of the formula ##STR6## wherein Q and R 3 are as defined above and Z is an oxygen protecting group, comprising reacting a compound of the formula wherein W is bromo or iodo, and Q is as defined above, with lithium metal or an alkyl lithium reagent.
  • the present invention also relates to a process for preparing a compound of the formula ##STR7## wherein the sterochemistry at the carbon labelled "3" is either pure in an absolute sense or a 1:1 mixture of R and S forms, and wherein R 3 is hydrogen or (C 1 -C 4 )alkyl, comprising reacting a compound of the formula ##STR8## having the same stereochemistry at the carbon labeled "3" as the desired compound of formula VII, and wherein R 3 is defined as above and Q is chloro, bromo, fluoro or OX, wherein X is SO 2 R 4 and R 4 is (C 1 -C 4 )alkyl, trifluoromethyl, or phenyl optionally substituted with 1 to 3 substituents independently selected from (C 1 -C 4 )alkyl, chloro and nitro, with a base.
  • Suitable bases include sodium hydride, potassium hydride, lithium diisopropyl amide, lithium hexamethyldisilazide
  • the present invention also relates to a process for preparing a pure enantiomer or a racemic mixture of a compound of the formula ##STR9## wherein R 3 is as defined above, comprising reacting a compound of the formula VII above, having the same stereochemistry at the carbon labeled "3" as the desired compound of formula VIII, with a suitable oxidizing reagent such as pyridinium chlorochromate, Jones reagent or manganese dioxide.
  • a suitable oxidizing reagent such as pyridinium chlorochromate, Jones reagent or manganese dioxide.
  • the present invention also relates to a process for preparing a pure enantiomer of a compound of the formula ##STR10## wherein R 3 is as defined above, comprising:
  • reaction scheme illustrates the novel processes and the preparation of the novel intermediates of the present invention. It also illustrates the method by which such processes and intermediates can be used to prepare the spiroheteroazolones disclosed in European Patent Application No. 88307985.7.
  • novel compounds of this invention are included in the generic formulas designated II, IV, V, VII and VIII in the reaction scheme.
  • the novel processes of this invention are represented by steps C, E and F of the reaction scheme.
  • the first step (A) in the sequence involves reacting the appropriate compound of formula I, wherein W is bromo or iodo, with water in the presence of a suitable diazotizing reagent to produce compounds of the formulae II and III, wherein W is bromo or iodo.
  • a suitable diazotizing reagent examples include t-butyl nitrite, sulfuric acid/sodium nitrite and hydrochloric acid/sodium nitrite.
  • the preferred diazotizing agent is hydrochloric acid/sodium nitrite. This step is generally carried out at a temperature from about -10° C. to about 50° C, preferably at about 0° C.
  • step (B) The compounds of formulae II and III are then reacted in step (B) with a suitable chlorinating or brominating reagent in the presence of an appropriate polar aprotic reaction inert solvent.
  • Suitable chlorinating reagents are POCl 3 , PCl 3 and PCl 5 .
  • POCl 3 is preferred.
  • Suitable brominating agents are POBr 3 and PBr 3 .
  • POBr 3 is preferred.
  • Suitable solvents include dimethylformamide, dimethylacetamide and N-methylpyrrolidinone, with dimethylformamide being preferred.
  • this step is carried out at a temperature from about 0° C. to about 100° C., with about 70° C. being preferred.
  • Step (B) produces a compound of the formula IV, wherein W is bromo or iodo.
  • the compound of formula IV so formed is then treated in Step (C) with lithium metal or an alkyl lithium reagent, in the presence of an aprotic non-polar reaction inert solvent, to form a 3-lithiated pyridine.
  • Suitable alkyl moleties of the alkyl lithium include (C 1-C 6 )alkyl.
  • the alkyl moiety of the alkyl lithium is n-butyl. This reaction is typically carried out at a temperature from about -100° C. to about -20° C. The preferred temperature is -78° C.
  • Suitable solvents include di-isopropyl ether, di-ethyl ether and tetrahydrofuran, with di-isopropyl ether and di-ethyl ether being preferred.
  • a compound of the formula ##STR14## wherein Z is a negative change or an oxygen protecting group is then added to the 3-1ithiated pyridine to produce a compound of the formula V, wherein Z a negative charge or an oxygen protecting group.
  • suitable oxygen protecting groups include trisubstituted silyl (e.g., t-butyldimethylsilyl), tetrahydropyranyl, methoxyethoxymethyl, ethoxyethyl, methoxymethyl and benzyl.
  • Step (C) is generally carried out at temperatures from about -100° C. with about -20° C., with about -78° C. being preferred.
  • the carbon to which R 3 is attached in the compound having the formula ##STR15## is a chiral center.
  • the compound of formula V formed in step (C) will have the same absolute stereochemistry at this chiral center as the aldehyde from which it was formed. As shown in the reaction scheme, this stereochemistry will be retained through the entire reaction sequence in the compounds having formulae VI, VII, VIII and IX. Therefore, either racemic mixtures or the pure enantiomers of compounds VIII and IX may be prepared by the method illustrated in the reaction scheme and described herein, depending upon stereochemistry of the aldehyde used in step (C).
  • step (D) The compound of formula V, wherein Z is an oxygen protecting group, is then reacted in step (D) with a suitable desilylating agent in the presence of a reaction inert solvent to form a compound of the formula V, wherein Z is hydrogen (also designated as formula VI in the reaction scheme).
  • suitable desilylating agents include tetra-n-butyl ammonium fluoride, hydrofluoric acid and cesium fluoride.
  • the preferred desilylating agent is tetra-n-butyl ammnonium fluoride.
  • suitable solvents are acetonitrile, methanol and tetrahydrofuran, with tetrahydrofuran being preferred.
  • Step (D) is typically carried out at temperatures from about -20° C. to about 50° C, with about -5° C. being preferred.
  • Compounds of the formula V, wherein Z is a negative charge may be prepared by deprotonating the corresponding compounds of the formula V, wherein Z is hydrogen (i.e., compounds of the formula VI) with an appropriate base.
  • appropriate bases are sodium. hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilylazide, and potassium hexamethyldisilylazide.
  • appropriate solvents for this reaction are tetrahydrofuran, dimethylformamide, isopropyl ether and diethyl ether.
  • Step (E) is then treated in Step (E) with a suitable base in the presence of a reaction inert polar solvent, to form a compound of the formula VII.
  • suitable solvents include dimethylformamide, dimethylsulfoxide and (C 1 -C 4 )alcohols. Tert-butanol is preferred.
  • Suitable bases include potassium t-butoxide, NaH, n-butyl-lithium, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene and potassium hexamethyldisilazide. Potassium t-butoxide is preferred.
  • Step (E) is typically carried out at a temperatures from about 0° C. to about 100° C., preferably at about 83° C.
  • the compound of formula VII is then reacted in Step (F) with a suitable oxidizing reagent (e.g., pyridinium chlorochromate, Jones reagent or manganese dioxide) in the presence of a reaction inert solvent (e.g.,CH 2 Cl 2 , acetone or toluene) to yield a compound of the formula VIII.
  • a suitable oxidizing reagent e.g., pyridinium chlorochromate, Jones reagent or manganese dioxide
  • a reaction inert solvent e.g.,CH 2 Cl 2 , acetone or toluene
  • the compounds of the Formula VIII so formed may be condensed with an alkali metal cyanide (e.g. sodium cyanide or potassium cyanide) and ammonium carbonate to form a spiro-imidazolidinedione product having the formula IX.
  • This reaction illustrated in step (G), is typically carried out in the presence of a reaction-inert polar organic solvent.
  • a reaction-inert polar organic solvent include cyclic ethers such as dioxane and tetrahydrofuran, lower alkylene glycols like ethylene glycol, water miscible lower alkanols such as methanol, as well as N,N-di(lower alkyl) lower alkanoamides such as N,N-dimethylacetamide.
  • this reaction is conducted at temperatures from about 25° C. to about 150° C.
  • the desired product is isolated in a conventional manner, by dilution with ice water and acidification. Further purification can be carried out by silica gel column chromatography.
  • the spiro-imidazolidinedione compounds of formula IX are aldose reductase inhibitors and are useful in lowering sorbitol levels in the sciatic nerve, retina and lens of diabetic subjects.
  • Examples of such compounds are (+) -cis-6'-chloro-2', 3'-dihydro-2'-methyl-spiro- [imidazolidine-4,4'-4'H-pyrano-2,3-b]pyridine]-2,5-dione (where cis means that 2'-methyl and 4'-NH are on the same side of the pyran ring) , (+) -trans-6'-chloro-2', 3'-dihydro-2'-methylspiro-[imidazolidine-4,4'-4'H-pyrano[2,3-b]-pyridine]-2,5-dione (where trans means that 2'-methyl and 4'-NH are on opposite sides of the pyran ring), (+)-cis-6'-
  • reaction pressures will be about 0.5 to about 3 atmospheres , preferably ambient pressure (i.e., about one atmosphere).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The present invention relates to processes and intermediates for the preparation of spiro-heteroazolones. The latter compounds are useful as aldose reductase inhibitors.

Description

This is a continuation of application Ser. No. 07/750,787, filed on Aug. 27, 1991, now abandoned, which is a division of U.S. Ser. No. 07/490,906 filed on Mar. 7, 1990, now U.S. Pat. No. 5,068,333.
BACKGROUND OF THE INVENTION
The present invention relates to processes and intermediates for the preparation of spiro-heteroazolones. The latter compounds are useful as aldose reductase inhibitors.
Spiro-heteroazolones that may be prepared by the processes disclosed herein are disclosed in European Patent Application No. 88307985.7, assigned to Pfizer Inc.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula ##STR1## wherein B is hydroxide, chloro or bromo.
The present invention also relates to a compound of the formula ##STR2## wherein R3 is hydrogen or (C1 -C4)alkyl
The present invention also relates to a compound of the formula ##STR3## wherein R3 is (C1 -C4) alkyl; Q is chlorine, bromine, or fluorine or OX, wherein X is SO2 R4 and R4 is (C1 -C4)alkyl, trifluoromethyl or phenyl optionally substituted with 1 to 3 substituents independently selected from (C1 -C4)alkyl, chloro and nitro; and Z is a negative charge, hydrogen, or an oxygen protecting group (e.g., a silyl-containing group such as t-butyldimethylsilyl).
The present invention also relates to a pure enantiomer of a compound of the formula ##STR4## wherein R3 is (C1 -C4) alkyl.
The present invention also relates to a compound of the formula: ##STR5## wherein R3 is methyl and wherein the stereochemistry of the carbon at position 3 is pure in an absolute sense and may be of either the R or S configuration.
The present invention also relates to a process for preparing a compound of the formula ##STR6## wherein Q and R3 are as defined above and Z is an oxygen protecting group, comprising reacting a compound of the formula wherein W is bromo or iodo, and Q is as defined above, with lithium metal or an alkyl lithium reagent.
The present invention also relates to a process for preparing a compound of the formula ##STR7## wherein the sterochemistry at the carbon labelled "3" is either pure in an absolute sense or a 1:1 mixture of R and S forms, and wherein R3 is hydrogen or (C1 -C4)alkyl, comprising reacting a compound of the formula ##STR8## having the same stereochemistry at the carbon labeled "3" as the desired compound of formula VII, and wherein R3 is defined as above and Q is chloro, bromo, fluoro or OX, wherein X is SO2 R4 and R4 is (C1 -C4)alkyl, trifluoromethyl, or phenyl optionally substituted with 1 to 3 substituents independently selected from (C1 -C4)alkyl, chloro and nitro, with a base. Suitable bases include sodium hydride, potassium hydride, lithium diisopropyl amide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, and other non-nucleophilic bases.
The present invention also relates to a process for preparing a pure enantiomer or a racemic mixture of a compound of the formula ##STR9## wherein R3 is as defined above, comprising reacting a compound of the formula VII above, having the same stereochemistry at the carbon labeled "3" as the desired compound of formula VIII, with a suitable oxidizing reagent such as pyridinium chlorochromate, Jones reagent or manganese dioxide.
The present invention also relates to a process for preparing a pure enantiomer of a compound of the formula ##STR10## wherein R3 is as defined above, comprising:
a) reacting a compound of the formula ##STR11## having the same absolute stereochemistry at the carbon labelled "3" as the desired compound of formula IX and wherein R3 is as defined above, with a suitable oxidizing reagent such as pyridinium chlorochromate, Jones reagent or manganese dioxide, to form a pure enantiomer of a compound of the formula ##STR12## having the same absolute stereochemistry at the carbon labelled "3" as the desired compound of formula IX, and (b) condensing said compound of formula VIII with an alkali metal cyanide (e.g. sodium cyanide or potassiura cyanide) and ammonium carbonate.
DETAILED DESCRIPTION OF THE INVENTION
The following reaction scheme illustrates the novel processes and the preparation of the novel intermediates of the present invention. It also illustrates the method by which such processes and intermediates can be used to prepare the spiroheteroazolones disclosed in European Patent Application No. 88307985.7.
The novel compounds of this invention are included in the generic formulas designated II, IV, V, VII and VIII in the reaction scheme. The novel processes of this invention are represented by steps C, E and F of the reaction scheme.
Except where otherwise noted, R3 R4, W, X, Z, and Q in the reaction scheme and discussion that follow are defined as above. ##STR13##
The first step (A) in the sequence involves reacting the appropriate compound of formula I, wherein W is bromo or iodo, with water in the presence of a suitable diazotizing reagent to produce compounds of the formulae II and III, wherein W is bromo or iodo. Examples of such reagents are t-butyl nitrite, sulfuric acid/sodium nitrite and hydrochloric acid/sodium nitrite. The preferred diazotizing agent is hydrochloric acid/sodium nitrite. This step is generally carried out at a temperature from about -10° C. to about 50° C, preferably at about 0° C.
The compounds of formulae II and III are then reacted in step (B) with a suitable chlorinating or brominating reagent in the presence of an appropriate polar aprotic reaction inert solvent. Suitable chlorinating reagents are POCl3, PCl3 and PCl5. POCl3 is preferred. Suitable brominating agents are POBr3 and PBr3. POBr3 is preferred. Suitable solvents include dimethylformamide, dimethylacetamide and N-methylpyrrolidinone, with dimethylformamide being preferred. Generally, this step is carried out at a temperature from about 0° C. to about 100° C., with about 70° C. being preferred. Step (B) produces a compound of the formula IV, wherein W is bromo or iodo.
The compound of formula IV so formed is then treated in Step (C) with lithium metal or an alkyl lithium reagent, in the presence of an aprotic non-polar reaction inert solvent, to form a 3-lithiated pyridine. Suitable alkyl moleties of the alkyl lithium include (C1-C 6)alkyl. In preferred embodiments of the present invention, respectively, the alkyl moiety of the alkyl lithium is n-butyl. This reaction is typically carried out at a temperature from about -100° C. to about -20° C. The preferred temperature is -78° C.
Suitable solvents include di-isopropyl ether, di-ethyl ether and tetrahydrofuran, with di-isopropyl ether and di-ethyl ether being preferred. A compound of the formula ##STR14## wherein Z is a negative change or an oxygen protecting group, is then added to the 3-1ithiated pyridine to produce a compound of the formula V, wherein Z a negative charge or an oxygen protecting group. Examples of suitable oxygen protecting groups include trisubstituted silyl (e.g., t-butyldimethylsilyl), tetrahydropyranyl, methoxyethoxymethyl, ethoxyethyl, methoxymethyl and benzyl. Step (C) is generally carried out at temperatures from about -100° C. with about -20° C., with about -78° C. being preferred.
The carbon to which R3 is attached in the compound having the formula ##STR15## is a chiral center. The compound of formula V formed in step (C) will have the same absolute stereochemistry at this chiral center as the aldehyde from which it was formed. As shown in the reaction scheme, this stereochemistry will be retained through the entire reaction sequence in the compounds having formulae VI, VII, VIII and IX. Therefore, either racemic mixtures or the pure enantiomers of compounds VIII and IX may be prepared by the method illustrated in the reaction scheme and described herein, depending upon stereochemistry of the aldehyde used in step (C).
The compound of formula V, wherein Z is an oxygen protecting group, is then reacted in step (D) with a suitable desilylating agent in the presence of a reaction inert solvent to form a compound of the formula V, wherein Z is hydrogen (also designated as formula VI in the reaction scheme). Suitable desilylating agents include tetra-n-butyl ammonium fluoride, hydrofluoric acid and cesium fluoride. The preferred desilylating agent is tetra-n-butyl ammnonium fluoride. Examples of suitable solvents are acetonitrile, methanol and tetrahydrofuran, with tetrahydrofuran being preferred. Step (D) is typically carried out at temperatures from about -20° C. to about 50° C, with about -5° C. being preferred.
Compounds of the formula V, wherein Z is a negative charge, may be prepared by deprotonating the corresponding compounds of the formula V, wherein Z is hydrogen (i.e., compounds of the formula VI) with an appropriate base. Examples of appropriate bases are sodium. hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilylazide, and potassium hexamethyldisilylazide. Examples of appropriate solvents for this reaction are tetrahydrofuran, dimethylformamide, isopropyl ether and diethyl ether.
The compound of formula VI, wherein Z is hydrogen, is then treated in Step (E) with a suitable base in the presence of a reaction inert polar solvent, to form a compound of the formula VII. Suitable solvents include dimethylformamide, dimethylsulfoxide and (C1 -C4)alcohols. Tert-butanol is preferred. Suitable bases include potassium t-butoxide, NaH, n-butyl-lithium, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene and potassium hexamethyldisilazide. Potassium t-butoxide is preferred. Step (E) is typically carried out at a temperatures from about 0° C. to about 100° C., preferably at about 83° C.
The compound of formula VII is then reacted in Step (F) with a suitable oxidizing reagent (e.g., pyridinium chlorochromate, Jones reagent or manganese dioxide) in the presence of a reaction inert solvent (e.g.,CH2 Cl2, acetone or toluene) to yield a compound of the formula VIII. This reaction is generally performed at temperatures from about -10° C. to about 100° C., with about 25° C. being preferred.
The compounds of the Formula VIII so formed may be condensed with an alkali metal cyanide (e.g. sodium cyanide or potassium cyanide) and ammonium carbonate to form a spiro-imidazolidinedione product having the formula IX. This reaction, illustrated in step (G), is typically carried out in the presence of a reaction-inert polar organic solvent. Appropriate solvents include cyclic ethers such as dioxane and tetrahydrofuran, lower alkylene glycols like ethylene glycol, water miscible lower alkanols such as methanol, as well as N,N-di(lower alkyl) lower alkanoamides such as N,N-dimethylacetamide. In general, this reaction is conducted at temperatures from about 25° C. to about 150° C. Upon completion of the reaction, the desired product is isolated in a conventional manner, by dilution with ice water and acidification. Further purification can be carried out by silica gel column chromatography.
The spiro-imidazolidinedione compounds of formula IX are aldose reductase inhibitors and are useful in lowering sorbitol levels in the sciatic nerve, retina and lens of diabetic subjects. Examples of such compounds are (+) -cis-6'-chloro-2', 3'-dihydro-2'-methyl-spiro- [imidazolidine-4,4'-4'H-pyrano-2,3-b]pyridine]-2,5-dione (where cis means that 2'-methyl and 4'-NH are on the same side of the pyran ring) , (+) -trans-6'-chloro-2', 3'-dihydro-2'-methylspiro-[imidazolidine-4,4'-4'H-pyrano[2,3-b]-pyridine]-2,5-dione (where trans means that 2'-methyl and 4'-NH are on opposite sides of the pyran ring), (+)-cis-6'-fluoro-2', 3'-dihydro-2'-methyl-spiro- [imidazolidine-4,4'-4'H-pyrano[2,3-b]pyridine]-2,5-dione, (+)-cis6'-bromo-2', 3'-dihydro-2'-methyl-spiro- [imidazolidine-4,4'-4'H-pyrano[2,3-b]pyridine]-2,5-dione, (4'S) (2'R) -6 '-chloro-2', 3'-dihydro-2'-methyl-spiro- [imidazolidine-4,4'-4'H-pyrano [2,3-b]-pyridine]-2,5-dione and (4'S) (2'R)-6'-chloro-2', 3'-dihydro-2'-methyl-spiro[imidazolidine-4,4'-4'H-pyrano-[2,3-b]pyridine]-2,5-dione-8'-oxide.
Unless indicated otherwise, the pressures of the foregoing reactions are not critical. Generally, the reaction pressures will be about 0.5 to about 3 atmospheres , preferably ambient pressure (i.e., about one atmosphere).
The following Examples are illustrative of the compounds and processes of the present invention. All melting points are uncorrected.
EXAMPLE 1 2-Amino-3-bromo-5-chloropyridine
An acetic acid (400 mL) suspension of sodium acetate (57.1 g, 0.696 mol) and 2-amino-5-chloropyridine (89.5 g, 0.696 mol) was treated with a solution of bromine (35.9 mL, 0.696 mol) in acetic acid (15 mL) over a period of 1.25 hours with gentle warming to 43° C. The resulting orange slurry was then cooled to 15° C. and filtered to provide a solid which was subsequently dissolved in water, basified (pH 8.5 ) with 1N NaOH, and extracted with ethyl acetate (5×150 mL). The combined organic layers were washed with 10% sodium bisulfite (2×150 mL), dried over magnesium sulfate, and condensed to give 102.1 g (70.7%) of a yellow solid, m.p. 83°-85° C.: IR(CHCl3) 3683, 3504, 3401, 2987, 2482, 2392, 1608, 1571, 1544, 1455, 1389, 1316, 1207, 1127, 1057, 1026, 895, 881, 650, 607, 249, 236cm ; H NMR (300MHz, CDCl3)δ 5.20 (br s, 2H) , 7.70 (d, 1H), J=2.2Hz) , 8.0 (d, 1H, J=2.2 Hz); 13 C NMR (CDCl3)δ 104.08, 120.33, 139.62, 145.24, 154.10; exact mass calculated for C5 H4 N2 BrCl=205.9246. High resolution mass spec. 205. 9246.
EXAMPLE 2 3-Bromo-5-Chloropyridin-2-One
To a cooled (0° C.) solution of 2-amino-3-bromo-5-chloropyridine (100 g, 0.482 tool) in water (815 mL) and concentrated HC1 (130 mL) was added a solution of sodium nitrite (33.26 g, 0.482 tool) in water (272 mL). The resulting suspension was allowed to warm to room temperature and stir for 18 hours, at which point the solids were filtered, washed with carbon tetrachloride (2×50 mL), and dried in a vacuum oven (40° C.) to yield 75.1 g (74.8%) of gray-yellow so lid, m.p. 170°-173° C.: IR (mineral oil (Nujol (trademark ) ) 3111, 3041, 2947, 2850, 2722, 1814, 1696, 1663, 1643, 1585, 1527, 1462, 1377, 1302, 1234, 1171, 1153, 1123, 1106, 1040, 917, 896, 876, 839, 747, 726, 644, 635, 561, 539, 523, 410, 251, 235, 225, 220cm-1 ; 1 H NMR (300 MHz, D6 -DMSO)δ 7.72 (d, 1H, J=2.2Hz) , 8.08 (d, 1H , J=2 . 2Hz ), 12.41 (br s, 1H); 13 C NMR (DMSO) δ 110.88, 115.35, 134.08, 142.64, 157.56; exact mass calculated for C5 H3 NBrClO=206.9086. High resolution mass spec. 206.9093.
EXAMPLE 3 3-Bromo-2,5-Dichloropyridine
To a solution of 3-bromo-5-chloropyridin-2-one (84.3 g, 0.404 tool) in DMF (100 mL) was added POCl3 (56.5 mL, 0.61 tool) via dropping funnel over 3 hours at room temperature. The resulting black solution was then heated to 70° C. and allowed to stir for 3 days. After cooling to room temperature, the solution was poured into 1L of ice/water, filtered, and the solid dried in a vacuum oven to provide 81.76 g (89%) of the desired 3-bromo-2, 5-dichloropyridine as an off-white solid, m.p. 39°-41° C.: IR(CHCl3) 3867, 3663, 2989, 2734, 1812, 1606, 1547, 1400, 1366, 1230, 1155, 1129, 1074, 1027, 894, 658, 563cm ; HNMR (300 MHz, CDCl3)δ 8.0 (d, 1H, J=2.2Hz) , 8.35 (d, 1H, J=2.2Hz); 13 C NMR (CDCl3)δ 120.43, 130.74, 141.46, 146.64, 148.99; exact mass calculated for C5 H2 NBrCl2 =224.8748; high resolution mass spec. 224.8764.
EXAMPLE 4 3- [3(R)-t-Butyldimethylsiloxy, 1-Hydroxybutyl]-2,5-Dichloropyridine
To a cooled (-70° C.) solution of n-butylithium (129.3 mL of 1.18M hexanes solution, 0.153 mol) in isopropyl ether was added a solution of 3-bromo-2,5-dichloropyridine (36.45 g, 0,161 mol) in isopropyl ether (225 mL) over a period of 30 minutes. The resulting white suspension was then treated with a solution of 3 (R) -t-butyldimethylsiloxybutyraldehyde (34.14 g, 0,169 tool) in isopropyl ether (106 mL) and allowed to stir for an additional 30 minutes at -70° C. followed by warming to room temperature. After the addition of 480 mL of water, the biphasic mixture was separated and the organic layer was extracted with isopropyl ether (2×200 mL). The combined organic layers were washed once with water, heated with decolorizing carbon [G-60 DARCO (trademark)] filtered through diatomateous earth [Celite (trademark)] and condensed on a rotary evaporator. The resulting hazy yellow liquid was heated at 80° C. under high vacuum overnight to yield the desired product (mixture of diastereomers) as an amber oil (40.52 g, 72%): Rf 0.36 (25% Et2 O in hexanes); 1 H NMR (60 MHz, CDCl3)δ 0.1 (s, 6H), 0.82 (s, 9H) , 1.18 (m, 3H) , 1.72 (m, 2H) , 4.16 (m, 1H) , 4.42 (m, 1H) , 5.10 (m, 1H) , 7.92 (d, 1H, J=2.6 Hz) , 8.13 (d, 1H, J=2.6 Hz) .
EXAMPLE 5 2,5-Dichloro-3-[3(R)-Hydroxy-1-Hydroxy1-Butyl]Pyridine
To a cooled (5° C.) THF (tetrahydrofuran) (161.5 mL) solution of the title compound of Example 4 (40.38 g, 0.115 mmol) was added 115.3 mL of a 0.1M solution of tetrabutylammonium fluoride in THF. Following warming to room temperature and stirring for 2.5 hours, the clear dark solution was condensed on a rotary evaporator and then reduced further under high vacuum. After the resulting oil was dissolved in water and extracted with Et2 O (ethyl ether) (2×150 mL), the combined organic extracts were washed once with water, concentrated to an oil, and chromatographed (70-230 mesh silica gel, 10% Et2 O in CH2 Cl2) to provide the product as a semi-solid (16.8 g, 61.7%) mixture of diastereomers): Rf 0.35 and 0.22 (25% Et2 O in CH2 Cl2); 1 H NMR (250 MHz, CDCl3)δ 1.30 (m, 6H) , 1.53 (m, 2H) , 1.96 (m, 2H), 2.42 (m, 1H), 2.73 (m, 1H), 4.10 (m, 1H) , 4.28 (m, 1H), 4.30 (s, 1H), 4.63 (d, 1H, J=4.5 Hz), 5.18 (m, 1H), 5.31 (m, 1H), 8.02 (d, 1H, J=2.6 Hz), 8.24 (m, 1H).
EXAMPLE 6 6-Chloro-3,4-Dihydro-4-Hydroxy-2 (R) -Methyl-2H) -Pyrano[2, 3-b]Pyridine
To a mixture of the title compound of Example 5 (16.4 g, 0.069 tool) and tert-butyl alcohol (115 mL) was added 23.39 g (0.208 mol) of potassium t-butoxide. After heating at reflux for 3 hours, the reaction was concentrated, diluted with water (150 mL) and extracted with isopropyl ether (3×150 mL). The combined extracts were washed with water, dried over MgSO4 and concentrated to a clear oil which was chromatographed (70-230 silica gel, CH2 Cl2 as eluent) to yield 10.8 g (78%) of the desired product as a mixture of diastereomers: Rf 0.39 (25% Et2 O in CH2 Cl2); 1 H NMR (250 MHz, CDCl3) 1.47 (d, 3H, J=6.3 Hz), 1.49 (d, 3H, J=6.3 Hz), 1.78 (m, 2H), 2.08 (m, 2H), 3.02 (d, 1H, J=4.5 Hz), 3.15 (d, 1H, J=7.7Hz), 4.39 (m, 1H), 4.58 (m, 1H), 4.80 (m, 1H), 4.93 (m, 1H), 7.64 (d, 1H, J=2.6 Hz), 7.83 (d, 1H, J=2.6 Hz), 8.00 (d, 1H, J=2.6 Hz), 8.08 (d, 1H, J=2.6 Hz).
EXAMPLE 7 6-Chloro-3,4-Dihydro-2 (R) -Methyl-4-Oxo-2H-Pyrano[2,3-b]Pyridine
To a suspension of the title compound of Example 6 (10.56 g, 0. 0529 tool) and diatomaceous earth [Celite (trademark)](14.25 g) in CH2 Cl2 (106 mL) was added pyridinium chlorochromate (28.51 g, 0,132 mol) at room temperature. After stirring for two hours, the reaction mixture was filtered through a pad of silica gel (100 g, 230-400 mesh) and condensed on a rotary evaporator. The crude white solid was recrystallized from isopropyl ether to yield 8.15 g (78%) of the pure azachromanone, m.p. 85°-87° C.: []D=+73.8° (c=1.0, methanol), Rf 0.28 (50% Et2 O in hexanes); 1 H NMR (250 MHz, CDCl3) 1.55 (d, 3H, J=7.0 Hz) , 2.67 (m, 2H) , 4.67 (m, 1H) , 8.08 (d, 1H, J=2.6 Hz) , 8.32 (d, 1H, J=2.6 Hz); Mass spec. 197 (M+); Anal. Calculated for C9 H8 ClNO2 : C, 54.70; H, 4.08. Found: C, 54.74; H, 4.13.
EXAMPLE 8 2 , 3-Dibromo-5-Chloropyridine
3-Bromo-5-chloropyridone (8.0 g, 38.4 mmole) was dissolved in dimethylformamide (60 ml) at ambient temperature. Phosphorus (V) tribromide oxide (16.5 g, 57.6 mmoles) was added and the reaction heated to 80° C. for 72 hours. After cooling, the reaction was poured onto 800 g of ice. Vacuum filtration provided the product as a dark solid (6.85 g). Hexane (225 ml) and decolorizing carbon was added to the crude product and the contents heated to reflux and then filtered through celite. The clear colorless filtrate was stripped under vacuum to yield the product as a white solid
1H NMR (250 MHz , CDC13) (5.3 g, 51%) m.p. 39.5-43° C. 1 H NMR (250 MHz, CDCl3) 1 H 8.28 (d, J=2 Hz), 7.89 (d, J=2 Hz); 13 C NMR (CDCl3) 146.93, 141.45, 141.02, 131.34, 124.01; Anal. Calculated for C5 H2 Br2 ClN: C, 22.13; H, 0.74; N, 5.16. Found C, 21.93; H, 0.53; N, 4.90. IR (neat) 3060, 1538, 1405, 1370, 1135, 1030, 905 cm ; Mass spec., (relative intensity) 269 (M+, 68), 190 (100), 111 (83).

Claims (4)

We claim:
1. A compound of the formula having the S configuration ##STR16## wherein R3 is (C1 -C4) alkyl.
2. A compound according to claim 1, wherein R3 is methyl.
3. A compound according to claim 2, wherein the stereochemistry of the carbon at position 3 is pure in an absolute sense and is the configuration.
4. A pure enantiomer of a compound of the formula ##STR17## wherein R3 is (C1 -C4)alkyl.
US07/961,049 1990-03-07 1992-10-14 Certain 3,4-dihydro-2H-pyrano[2,3-b]pyridines Expired - Fee Related US5336771A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US07/961,049 US5336771A (en) 1990-03-07 1992-10-14 Certain 3,4-dihydro-2H-pyrano[2,3-b]pyridines

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US07/490,906 US5068333A (en) 1990-03-07 1990-03-07 6-chloro-3,4-dihydro-pyrano [2,3-b]pyridines having the R configuration
US75078791A 1991-08-27 1991-08-27
US07/961,049 US5336771A (en) 1990-03-07 1992-10-14 Certain 3,4-dihydro-2H-pyrano[2,3-b]pyridines

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US75078791A Continuation 1990-03-07 1991-08-27

Publications (1)

Publication Number Publication Date
US5336771A true US5336771A (en) 1994-08-09

Family

ID=23949994

Family Applications (2)

Application Number Title Priority Date Filing Date
US07/490,906 Expired - Fee Related US5068333A (en) 1990-03-07 1990-03-07 6-chloro-3,4-dihydro-pyrano [2,3-b]pyridines having the R configuration
US07/961,049 Expired - Fee Related US5336771A (en) 1990-03-07 1992-10-14 Certain 3,4-dihydro-2H-pyrano[2,3-b]pyridines

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US07/490,906 Expired - Fee Related US5068333A (en) 1990-03-07 1990-03-07 6-chloro-3,4-dihydro-pyrano [2,3-b]pyridines having the R configuration

Country Status (10)

Country Link
US (2) US5068333A (en)
EP (1) EP0445950B1 (en)
JP (1) JPH0586031A (en)
AT (1) ATE106871T1 (en)
CA (1) CA2037590A1 (en)
DE (1) DE69102315T2 (en)
ES (1) ES2055529T3 (en)
FI (1) FI911124A (en)
IE (1) IE910740A1 (en)
PT (1) PT96948A (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11257361A (en) 1998-01-08 1999-09-21 Nippon Seiko Kk Sealing device for rolling bearing
CN103664765A (en) * 2013-12-06 2014-03-26 常熟市联创化学有限公司 Preparation method of 2-amino-3-bromopyridine
CN105061300B (en) * 2015-08-31 2018-02-16 南京红太阳生物化学有限责任公司 A kind of synthetic method of chloro-pyridine and its derivative

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0014079A1 (en) * 1979-01-22 1980-08-06 Pfizer Inc. Spiro-quinolylhydantoins, process for their preparation and pharmaceutical compositions thereof
FR2455046A1 (en) * 1979-04-25 1980-11-21 Science Union & Cie Quinoline, thiochromane, and benzopyran spiro hydantoin derivs. - having aldose reductase inhibiting activity
EP0040176A1 (en) * 1980-05-12 1981-11-18 Ciba-Geigy Ag Process for the preparation of 2,3,5-trichloropyridine
EP0097014A2 (en) * 1982-06-12 1983-12-28 Pfizer Limited Triazole antifungal agents
EP0136593A2 (en) * 1983-09-06 1985-04-10 The Dow Chemical Company Novel halopyridines and methods of making
EP0306251A2 (en) * 1987-09-04 1989-03-08 Pfizer Inc. Azolidinedione derivatives
US4980357A (en) * 1990-03-01 1990-12-25 Pfizer Inc. Azolidinedione derivatives

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0014079A1 (en) * 1979-01-22 1980-08-06 Pfizer Inc. Spiro-quinolylhydantoins, process for their preparation and pharmaceutical compositions thereof
FR2455046A1 (en) * 1979-04-25 1980-11-21 Science Union & Cie Quinoline, thiochromane, and benzopyran spiro hydantoin derivs. - having aldose reductase inhibiting activity
EP0040176A1 (en) * 1980-05-12 1981-11-18 Ciba-Geigy Ag Process for the preparation of 2,3,5-trichloropyridine
EP0097014A2 (en) * 1982-06-12 1983-12-28 Pfizer Limited Triazole antifungal agents
EP0136593A2 (en) * 1983-09-06 1985-04-10 The Dow Chemical Company Novel halopyridines and methods of making
EP0306251A2 (en) * 1987-09-04 1989-03-08 Pfizer Inc. Azolidinedione derivatives
US4980357A (en) * 1990-03-01 1990-12-25 Pfizer Inc. Azolidinedione derivatives

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, vol. 113, No. 3, Jul. 16, 1990. R. Sarges et al.: "Spiro Hydantoin Aldoso Reductase Inhibitors Derived from 8-aza-4-chromanones", p. 648; ref. No. 23773V & J. Med., 1990, 33[7], 1859-65 (abstract).
Chemical Abstracts, vol. 113, No. 3, Jul. 16, 1990. R. Sarges et al.: Spiro Hydantoin Aldoso Reductase Inhibitors Derived from 8 aza 4 chromanones , p. 648; ref. No. 23773V & J. Med., 1990, 33 7 , 1859 65 (abstract). *
Chemical Abstracts, vol. 67, No. 15, Oct. 9, 1967, Columbus, Ohio, USA, H. Sliwa: "Synthesis of New Heterocylic Compounds", p. 6926; ref. No. 73537Y & C. R. Acad. Sci., Paris, Ser. C 264 [23], 1893-5, [1967], abstract.
Chemical Abstracts, vol. 67, No. 15, Oct. 9, 1967, Columbus, Ohio, USA, H. Sliwa: Synthesis of New Heterocylic Compounds , p. 6926; ref. No. 73537Y & C. R. Acad. Sci., Paris, Ser. C 264 23 , 1893 5, 1967 , abstract. *
March, Advanced Organic Chemistry, Second Edition, pp. 98 113, McGraw Hill Publishes, 1979. *
March, Advanced Organic Chemistry, Second Edition, pp. 98-113, McGraw-Hill Publishes, 1979.

Also Published As

Publication number Publication date
FI911124A0 (en) 1991-03-06
US5068333A (en) 1991-11-26
EP0445950B1 (en) 1994-06-08
DE69102315T2 (en) 1994-09-15
FI911124A (en) 1991-09-08
ATE106871T1 (en) 1994-06-15
ES2055529T3 (en) 1994-08-16
PT96948A (en) 1991-10-31
DE69102315D1 (en) 1994-07-14
CA2037590A1 (en) 1991-09-08
IE910740A1 (en) 1991-09-11
EP0445950A1 (en) 1991-09-11
JPH0586031A (en) 1993-04-06

Similar Documents

Publication Publication Date Title
US5491237A (en) Intermediates in pharmaceutical camptothecin preparation
Buon et al. Synthesis of 3-Substituted and 2, 3-Disubstituted-4H-1, 4-Benzoxazines
US5336771A (en) Certain 3,4-dihydro-2H-pyrano[2,3-b]pyridines
US4650890A (en) Preparation of olefinic compounds and intermediates thereof
Miyamoto et al. Microbial asymmetric decarboxylation of fluorine-containing arylmalonic acid derivatives
US5212317A (en) Methods and intermediates for the assymmetric synthesis of camptothecin and camptothecin analogs
US5493048A (en) Fluoro-trifluoromethylbenzoic acid derivatives
JP3145822B2 (en) Method for producing 5-substituted 2-chloropyridines
US5162540A (en) Process for the production of (+) biotin
KR100186830B1 (en) Astaxantin intermediates
US5292911A (en) Monocyclic terpene derivatives
US5258516A (en) Optically pure D,E ring intermediates useful for the synthesis of camptothecin and camptothecin analogs
EP0095835A1 (en) Preparing 4,7-dialkoxybenzofurans, and intermediates used therein
JPS621392B2 (en)
US5486615A (en) Method of making asymmetric DE ring intermediates for the synthesis of camptothecin analogs
US5264579A (en) D ring intermediates for the synthesis of camptothecin and camptothecin analogs
JP3002750B2 (en) Indole derivatives
JP3723885B2 (en) Method for producing enol ether derivative
KR100355756B1 (en) Method for manufacturing a S-ofloxacin
EP0212868B1 (en) Process for preparing 2-acyl-3,4-dialkoxyanilines
KR840002124B1 (en) Process for preparing 4-phenyl-2(1h)-quinazolinones and-tetrahydro-2(1h)-quinazolinones
US6559309B2 (en) Preparation of a camptothecin derivative by intramolecular cyclisation
JPH0436260A (en) Propene derivative
JP3243979B2 (en) Optically active 3-oxy-5-oxo-6-heptenoic acid derivative and method for producing the same
JPH0588230B2 (en)

Legal Events

Date Code Title Description
FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

AS Assignment

Owner name: PFIZER INC., NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MURTIASHAW, CHARLES W.;QUALLICH, GEORGE J.;REEL/FRAME:006899/0220

Effective date: 19940214

LAPS Lapse for failure to pay maintenance fees
FP Lapsed due to failure to pay maintenance fee

Effective date: 19980809

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362